As Supplement GMP Implementation Hits Zero Hour, Small Firms Still Struggle

FDA's final rule for dietary supplement good manufacturing practices completed its phase-in for the industry June 25, and the agency now prepares to conduct inspections of small firms, which have struggled the most to comply with the regulation.

Meanwhile, FDA rolls along with audits of large and medium-sized companies, offering stakeholders an increasingly clearer picture of what GMP inspections will entail.

A spokesman for FDA's Center for Food Safety and Applied Nutrition said June 24 the agency has tallied 57 GMP inspections since the rule's first deadline - 7 inspections in 2008, 28 in 2009 and 22 so far in 2010.

Small companies with fewer than 20 employees should expect GMP inspections "beginning late this summer or in the fall, depending on competing priorities for the field's resources," the spokesman said in an e-mail.

The compliance deadline came first for supplement manufacturers with 500 or more employees, in June 2008; firms with more than 20 employees had a June 2009 deadline under the final ¹ rule.

What To Expect When FDA's Inspecting

FDA has sent two warning letters and four untitled letters to firms regarding violations of current GMPs; the second warning letter, to Atlas Operations in Pompano Beach, Fla., was posted to FDA's website June 22.

The letter details a spate of GMP violations FDA observed during an October-November 2009 inspection, including Atlas' lack of required information in its master manufacturing record for formulas, its use of expired dietary supplement components in production and its employees' unhygienic handling of components.

FDA's Florida district office also notes Atlas' products such as Rock Hard Weekend and Stamin It are unapproved drugs containing pharmaceutical ingredients. The company has run into trouble with FDA before, issuing recalls of several sexual enhancement products in December and April (² 'The Tan Sheet' April 19, 2010, In Brief).

Like the agency's first supplement GMP warning - to aloe products manufacturer Coats International Holdings in March - the Atlas letter holds few surprises and delineates many of CFSAN's stated priorities (³ (Also see "First GMP Warning Letter Reflects FDA's List Of Major Concerns" - Pink Sheet, 17 May, 2010.)).

The GMP warning letters are invaluable tools to study in advance of hosting an FDA inspection, experts say.

With GMPs still a new regulation, "certain information, I think, will only become available by the process of FDA inspecting firms" and detailing observations in inspection reports, said Washington-based food and drug attorney Holly Bayne.

Dean Cirotta, a VP of EAS Consulting Group, said the Compliance Program Guidance ⁴ Manual that CFSAN implemented March 26 to provide field investigators with inspection goals offers a window into what inspectors look for and what GMP deviations likely will earn a warning letter (⁵ (Also see "FDA's Reynolds Marks Top GMP Trouble Spots As Deadline Looms" - Pink Sheet, 10 May, 2010.)).

Additionally, "I think we're going to start seeing more consistent and more focused inspections across the board now that everybody has the guide available to them," Cirotta said.

A Fully Regulated Industry

Many supplement industry boosters marked June 25 as a day to celebrate, with hopes that allegations the industry is unregulated can finally be put to rest.

"This is a historic day for the dietary supplement industry and its consumers," said Council for Responsible Nutrition President and CEO Steve Mister.

"Clearly, there are stringent manufacturing standards that our entire industry must adhere to and we expect that, after three years of preparation for implementation, manufacturers are prepared to embrace GMP compliance," he added in a release.

Whether the smallest firms have fully absorbed the GMP final rule and can weather an FDA inspection remains unclear, however.

Smaller manufacturers generally are not ready for GMP implementation, said Martina LaGrange, a principal with the FDA Compliance Group consultancy in Littleton, Colo. And that opinion is based only on firms proactive enough to hire compliance consultants, she said.

The GMP final rule is "a big white elephant, and you've got to eat it one bite at a time," LaGrange said, explaining that small companies typically need a year to 18 months to achieve GMP compliance.

She advised executives at smaller firms with limited in-house resources to bring in consultants or educate themselves via industry-sponsored training.

Identity testing of dietary ingredients and qualification of suppliers remain the main stumbling blocks for small firms, said Shelly Maifarth, also a principal of FDA Compliance Group.

Some in the industry have suggested small supplement firms move toward a cooperative model for purchasing and testing ingredients, as a means of leveraging lower prices and sharing testing costs (⁶ (Also see "Looming GMPs Could Doom Some Firms Unless Industry, FDA Lend Support" - Pink Sheet, 16 Mar, 2009.)). Though this practice is becoming more common in the pharmaceutical industry, it has been slow to gain traction among supplement manufacturers.

Ingredient stability testing, especially for complex multi-component supplement products, is another "one of the 800-pound gorillas that dietary supplement companies, actually of all sizes, I think are struggling with," said William Ment, a senior consultant with Alexandria, Va.-based EAS.

Ment highlighted documentation as a separate challenge companies face. This includes training records to prove employees are qualified for certain tasks, written specifications for raw materials and packaging components, and documented rationales for why certain tests were not performed on a finished product.

Finally, supplier qualification remains somewhat enigmatic for small firms, Ment said, especially those tasked with auditing multiple vendors overseas.

"Are they allowed to prioritize them? Do they have to try to see all of them to qualify them? I think these are all questions the industry is struggling with, especially the smaller firms [asking], 'How do I go do 12 audits in China?'" Ment said.

Industry groups have sought to fill in the blanks many believe FDA left in the final rule's supplier qualification provision.

The Joint Standardized Information on Dietary Supplement Ingredients Working Group is developing a guidance, with some input from FDA, on best practices for qualifying ingredient vendors (⁷ (Also see "SIDI Group Expects "Passport" To Business Growth With Standardized CofA" - Pink Sheet, 14 Jun, 2010.)).

Land Of Confusion

Despite witnessing some struggles, Ment said he has been impressed with supplement firms' efforts to comply with GMPs.

Others, however, are less sanguine about the industry's hopes for passing muster with FDA.

Attorney Jonathan Emord sued the agency in August 2009, alleging the GMP final rule violates the Dietary Supplement Health and Education Act and does not give sufficient guidance to companies (⁸ (Also see "FDA's Frankos Grades GMP Complaint Recordkeeping "Needs Improvement"" - Pink Sheet, 23 Nov, 2009.)).

"Industry remains hopelessly confused as to whether steps taken in individual circumstances will be deemed sufficient by agency investigators," Emord said in an e-mail.

"I suspect that this is precisely as FDA would have it; at last it is 'taming' and 'subjugating' an industry that has long enjoyed a degree of liberty."

The Clifton, Va.-based attorney said FDA is expected to file its opposition to his motion for summary judgment July 1. The case was filed on behalf of several supplement industry stakeholders and interest groups in the U.S. District Court for the District of Columbia.

Ironically, Vasilios "Bill" Frankos, then head of FDA's Dietary Supplement Programs, said in November 2009 that Emord's complaint had delayed the agency's release of a GMP compliance guide for small supplement companies.

The FDA spokesman said the compliance guide remains under development, without an estimated publication date.

- Dan Schiff ( ⁹ [email protected] )